LXR and PPARgamma mediated Abeta clearance mechanisms

描述(申请人提供)：这项申请专注于阿尔茨海默病(AD)的新治疗方法的开发，目标是核受体、肝脏X受体(LXRs)和过氧化物酶体增殖物激活受体伽马(PPARy)。我们证明了用LXR激动剂治疗老年AD动物模型(Tg2576)后，A？肽水平和斑块负荷减少。我们发现，LXR激动剂从大脑中清除A？的能力依赖于ApoE。重要的是，我们展示了一种全新的机制，通过这一机制，ApoE促进了A？肽的蛋白降解。LXR激活导致ApoE和脂类转运蛋白ABCA1的转录诱导。ABCA1是载脂蛋白E通过脂化功能成熟所必需的，导致含有载脂蛋白E的高密度脂蛋白样颗粒的形成，这是胆固醇和磷脂在大脑中运输所必需的。A与载脂蛋白E以高亲和力结合，这种相互作用受载脂蛋白E的脂化状态控制。我们发现，脂化形式的载脂蛋白E通过依赖于Neprilysin的蛋白分解促进小胶质细胞对A？肽的细胞内降解。此外，我们还证明了脂化的ApoE通过胰岛素降解酶在细胞外对Aβ的降解起陪伴作用。相反，脂化较差的ApoE形式会形成稳定的、抗蛋白酶的复合体。重要的是，相关核受体PPARy的激动剂也可以引起类似的效应，我们假设PPARy参与了与LXR一起的一个积极的、自我增强的反馈环，以刺激ApoE的脂化和A？清除。这些数据建立了以前未知的ApoE的作用，促进了A？从脑中的蛋白分解清除，这可能是其参与AD发病的基础。我们建议建立LXR激动剂治疗的治疗参数，以预防和逆转AD动物模型中AD相关斑块病理的发展。我们将通过检测LXRs基因失活的AD小鼠模型来验证LXRs作为治疗靶点的有效性。我们将建立LXRs和PPARy靶向基因的机制，最突出的是ApoE和ABCA1，以促进A？清除。我们将测试PPARy对A？Clearance的操作是否从属于LXR功能，并依赖于LXR功能。

DESCRIPTION (provided by applicant): This application is focused on the development of new therapeutic approaches to Alzheimer's disease (AD) that target the nuclear receptors, liver X receptors (LXRs) and peroxisome proliferator-activated receptor gamma (PPARy). We demonstrate that treatment of an aged animal model of AD (Tg2576) with LXR agonists results in the reduction of A¿ peptide levels and plaque load. We show that the ability of LXR agonists to clear A¿ from the brain is reliant upon ApoE. Importantly, we demonstrate an entirely novel mechanism through which ApoE facilitates the proteolytic degradation of A¿ peptides. LXR activation results in the transcriptional induction of ApoE and the lipid transporter ABCA1. ABCA1 is required for the functional maturation of ApoE through its lipidation, leading to the formation of ApoE-containing HDL-like particles that are required for cholesterol and phospholipid trafficking in the brain. A¿ binds to ApoE with high affinity and this interaction is governed by the lipidation status of ApoE. We show that lipidated forms of ApoE facilitate the intracellular degradation of A¿ peptides by microglia through neprilysin- dependent proteolysis. Further, we demonstrate that the lipidated ApoE acts to chaperone the extracellular degradation of A¿ by insulin degrading enzyme. In contrast, poorly lipidated forms of ApoE form stable, protease resistant complexes. Importantly, agonists of the related nuclear receptor PPARy can elicit similar effects and we hypothesize that PPARy participates in a positive, self reinforcing, feed back loop with LXR to stimulate ApoE lipidation and A¿ clearance. These data establish a previously unrecognized action of ApoE, facilitating the proteolytic clearance of A¿ from the brain that may underlie its participation in AD pathogenesis. We propose to establish the therapeutic parameters for LXR agonist treatment to prevent and to reverse the development of AD-related plaque pathology in an animal model of AD. We will validate the LXRs as a therapeutic target by examination of murine models of AD in which LXRs have been genetically inactivated. We will establish the mechanisms through which the LXRs and PPARy target genes, most prominently ApoE and ABCA1, to facilitate A¿ clearance. We will test if the actions of PPARy on A¿ clearance are secondary to, and reliant upon, LXR function.